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Presenilin-2 (PSEN2)

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Presenilin-2 (PSEN2) is one of two highly homologous presenilin genes expressed in vertebrates. Presenilin-1 (PSEN1) has been more extensively studied in Alzheimer’s research because fewer mutations in PSEN2 are known. Mutations in the presenilin genes are the most common cause of familial Alzheimer’s disease, with more than 150 total mutations identified, of which about a dozen are in PSEN2. Mutations further differ from those in PSEN1 in that their onset age is somewhat later and their penetrance lower; that is, some mutation carriers do not develop Alzheimer’s disease.

Much information about these two proteins applies to both. Like presenilin-1, presenilin-2 forms the catalytic subunit of the γ-secretase complex that processes amyloid precursor protein (APP) and other integral membrane proteins. Comprising presenilin, nicastrin, aph-1, and pen-2, this large complex comprises one protein each of presenilin, nicastrin, aph-1, and pen-2; depending on which isoform of the four constituent proteins is used, this large complex occurs in different types. Besides presenilin, aph-1, too, comes in different forms, called aph-1a and aph-1b/c. Mice in which individual isoforms of these varying complex constituents have been deleted have different phenotypes. This suggests different substrate specificity of the respective complexes, giving clues to the differential function of presenilin-2 to presenilin-1. As part of γ-secretase, both presenilins can cleave APP to produce Aβ peptides and other proteolytic fragments, but the presenilins are thought to differ in their physiological roles. Presenilin-2 is generally expressed at lower levels than presenilin-1.